15alpha,16alpha-methylene steroids and processes for their production and use

ABSTRACT

WHEREIN R1 IS A HYDROGEN ATOMS OR SATURATED OR UNSATURATED ALKYL OF 1-4 CARBON ATOMS, AND PHYSIOLOGICALLY ACCEPTABLE 17-ESTERS THEREOF POSSESS HIGH ANDROGENIC ACTIVITY WITH RELATIVELY LOW ANABOLIC ACTIVITY. THEY CAN BE PRODUCED BY OXIDATION OF THE CORRESPONDING $4 AND $5-3-HYDROXYSTEROIDS AND BY ALKYLATION OF THE CORRESPONDING $5-3-ACYLOXY-17-KETO STEROIDS FOLLOWED BY HYDROLYSIS OF THE 3-ACYLOXY GROUP AND OXIDATION OF THE THUS-PRODUCED 3-HYDROXY GROUP.   3-(O=),15,16-(-CH2-),17-R1,17-HO-ANDROST-4-ENE   15A,16A-METHYLENE STEROIDS OF THE FORMULA

United States Patent O 3,749,742 150:,16zz-METHYLENE STEROIDS AND PROCESSES FOR THEIR PRODUCTION AND USE Rudolf Wiechert and Hermann Steinbeck, Berlin, Germany, assignors to Schering Aktiengesellschaft, Berlin,

Germany No Drawing. Filed Feb. 24, 1972, Ser. No. 229,205 Claims priority, application Germany, Feb. 24, 1971, P 21 09 555.6 Int. Cl. C07c 169/22 US. Cl. 260-3974 15 Claims ABSTRACT OF THE DISCLOSURE 15a,16u-methylene steroids of the formula BACKGROUND OF THE INVENTION This invention relates to novel 15u,16a-methylene steroids.

SUMMARY OF THE INVENTION The 15a,l6u-methylene compounds of this invention are steroids of the general Formula I wherein R is a hydrogen atom or saturated or unsaturated alkyl of 1-4 carbon atoms, and physiologically acceptable 17-esters thereof.

DETAILED DISCUSSION In addition to a hydrogen atom, R can be saturated or unsaturated alkyl of 1-4 carbon atoms, preferably 1-3, more preferably 1-2 carbon atoms, e.g., methyl, ethyl, propyl, butyl, vinyl, allyl, ethinyl, propinyl, etc.

Of the compounds of this invention, preferred are:

(a) free 17-hydroxy steroids of Formula I;

(b) those of Formula I wherein R is H, methyl, ethyl or ethinyl;

(c) esters of the free 17-hydroxy compounds of Formula I and an alkanoic acid of 1 to 15, preferably 2 to 11 carbon atoms, inclusive.

Since the 17-ester group can be subsequently saponified, it can be any esterified OH group. Preferred are esters of physiologically acceptable acids. Preferred acids are hydrocarbon carboxylic acids, e.g., of up to 15 carbon "ice atoms, preferably 2 to 11 carbon atoms. These acids can be aliphatic, cycloaliphatic, aromatic, or mixed aromaticaliphatic acids. Examples of such acids are straight or branched chain alkanoic, e.g., formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, undecyclic acid, trimethylacetic acid, diethylacetic acid, tert.-buty1acetic acid; aralkanoic, e.g., phenylacetic acid; cycloalkanoic, e.g., cyclopentylpropionic acid; and aryl, e.g., benzoic acid.

As is well known in steroid chemistry, when the free 17-OH steroid possesses the desired activity, the exact nature of the acyl moiety of an ester of such an active 17-OH compound is not critical. Thus, equivalents of the esters described above are esters corresponding to acids bearing one or more simple substituents which do not affect the fundamental character of the steroid. Thus, an acid described above can be substituted with halogen, e.g., mono-, dior tri-chloroacetic acid, or any other substituted acid which has been employed to form an ester of a 17-hydroxy steroid, and esters of amino acids, e.g., aminoactic acid, diethylamino-, piperidinoand morpholino-acetic acid, can be used to form water soluble half-esters. Also suitable are esters of the usual inorganic acids, such as, for example, sulfuric acid and phosphoric acid which also can be used to produce water soluble esters.

For the preparation of water-soluble products, the aminoacylates, e.g., diethylamino-, piperidino-, and morpholino-acetates, can be converted into their acid addition salts, e.g., hydrochloride, and the sulfuric acid esters and phosphoric acid esters and the esters of dibasic organic acids can be converted into their alkali metal, e.g., sodium, salts.

The compounds of Formula I and their physiologically acceptable 17-esters possess valuable therapeutic properties, including androgenic activity. They possess high androgenic effectiveness with a favorably differentiated anabolic effect, as evidenced by the experimental data set forth hereinbelow, comparing the activities of 17,8-hydroxy-l5a,16u-methylene-4-androsten-3-one (II) and 17B- acetoxy-15a,16a-methylene-3-androsten-3-one (III) with mesterolone (I) (17p-hydroxy-1u-methyl-5a-androstan-3- one). The experiments were conducted employing the conventional anabolic/androgenic test on juvenile castrated rats (Table 1) and the chicken comb test on oneday-old chickens (Table 2) after oral administration.

TABLE 1 Anabolic/androgenic test. Duration of administration: 12 days] Weights of organs in rug/ g.-

of body Weight Dose, Semim n Levaanimal/ vesi- Prostor No. Compound day ele tate ani Untreated control 6 l0 17 I Mesterolone 30 16 25 23 10 9 14 23 3 6 10 19 11------ 17fl-hydroxy-15a,16u- 30 34. 50 30 methylenei-androsten- 10 15 29 20 3-one. 3 8 17 17 III.. 17B-acetoxy-15a,16u- 30 28 44 25 methylene-t-androsten- 10 12 25 20 3-one. 3 8 17 19 TABLE 2 Comb weight in mgJg. of body weight at a dose of animal/day of- No. Compound 3 mg. 1 mg. 0.3 mg.

Untreated contr 0.35 I Mesterolone 0.70 0.65 0.56 II 17 3-hydroxy-15a,16amethylene-4- 1. 33 1.24 0.85

androsten-3-one. III 17B-acetoxy-15a,16a-methylene-4- 1. 47 1.11 0.68

androsten-3-one.

The compounds of this invention are distinguished in that they produce very minor undesired side effects. Consequently, they can be used, for example, for the treatment of the lessening of male functional power in middle age and old age; cardiac and circulatory disorders; potency disturbances; hypogonadism; convalescence; general exhaustion; chronic infectious diseases, e.g., asthma; cachectic conditions, such as, for example, occurring during radiation therapy; anemias; osteoporosis; chronic diseases of the liver and kidney; muscular dystrophy, etc.

The specific drugs are prepared in the usual manner by converting the effective agents, together with pharmaceutically acceptable additives, carriers and flavoring agents, into the desired forms of application, such as tablets, drages, capsules, solutions, ointments, etc. The concentration of effective agent in the thus-formulated drugs is dependent on the form of administration.

The compounds can be employed in the treatment of aforesaid conditions formulated in conventional pharmaceutically acceptable carriers in the form customarily employed in pharmaceuticals. For oral administration, especially suitable are tablets, drages, capsules, pills, suspensions and solutions. Suitable excipients for tablets are, for example, lactose, amylose, talc, gelatin, magnesium stearate, and the like.

For parenteral application, aqueous and oily solutions or suspensions can be employed.

The compounds of this invention are formulated so as to provide, for example, 1 to mg. of the effective agent in admixture with 15 mg. to 0.5 mg. of a pharmacologically indifferent excipient, i.e., a pharmaceutically acceptable carrier, per unit dosage, e.g., per tablet.

The novel la,l6a-methylene steroids of general Formula I and their 17-esters are preferably produced by oxidizing the 3-hydroxy group of a compound of general Formula II Ion, Y l H0 w y wherein R is H or saturated or unsaturated alkyl of 1-4 carbon atoms and R is H or acyl, and

CI- Cs Cs represents the grouping C C =C or C :C C and, optionally thereafter, a free 17;.8-hydroxy group (R =H) is esterified to a l7-ester group (R =acyl).

The oxidation of the 3-hydroxy group to a 3-keto group takes place employing conventional operating methods for the oxidation of A and A -3-hydroxy steroids. For example, a starting compound of Formula H can be oxidized with an aluminum alcoholate in the presence of a ketone. In this process, known as an Oppenauer oxidation, an aluminum alcoholate of a secondary or tertiary alcohol is preferably employed, e.g., aluminum isopropylate, aluminum tert.-butylate and aluminum phenolate, in combination with a lower aliphatic or isocyclic ketone, e.g., acetone, methyl ethyl ketone, cyclopentanone and cyclohexanone. In the Oppenauer oxidation, any A -double bond present in the starting material is rearranged into a A -double bond.

Starting compounds of Formula II can also be oxidized with chromic acid. In this oxidation, at lower carboxylic acid, e.g., acetic acid, is preferably employed as the solvent.

In case of starting compounds already possessing a A -double bond, other oxidation methods can, as is known, also be utilized for the oxidation of the 3-hydroxy group. Examples of such oxidation methods are: the oxidation with manganese (IV) oxide in an inert solvent, e.g.,

chloroform, methylene chloride, benzene, toluene, dioxane and tetrahydrofuran; oxidation with N-chlorosuccinimide in a polar solvent, e.g., acetone, dioxane, tetrahydrofuran, pyridine and dimethylformamide; and oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone in a solvent, e.g., tert.-butanol, dioxane and tetrahydrofuran.

The 3-hydroxy group can also be oxidized by a microbiological process, optionally with the simultaneous isomerization of the A -double bond, e.g., fermentation of the starting compound of Formula II with Flavobacterium dehydrogenans under the usual fermentation conditions.

The optional esterification of the 17-hydroxy group can be conducted in accordance with the known operating methods. Thus, the 17-hydroxy group can be esterified with acid chlorides or acid anhydrides in the presence of an acidic or basic esterification catalyst, e.g., hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, trifiuoroacetic acid, pyridine, collidine and lutidine. This esterification, as is known, takes place at a low temperature, preferably at a starting temperature of --20 C. However, the esterification can also be conducted at room temperature or at an elevated temperature, e.g., up to C.

The starting compounds of general Formula II wherein R is saturated or unsaturated lower alkyl of 14 carbon atoms can be produced preferably by the alkylation of a 3/3-acyloxy-15a,16u-methylene-5-androsten-17-one, e.g., wherein the acyloxy group is that of a hydrocarbon carboxylic acid of 1-8 carbon atoms, e.g., acetic acid, propionic acid, butyric acid, trimethylacetic acid and benzoic acid, with an alkylmagnesium compound. The alkylmagnesium compound means a haloalkylmagnesium compound with a lower saturated or unsaturated alkyl group. This Grignard reaction, is, as is known, generally effected in the presence of an ether, e.g., diethyl ether, diisopropyl ether, di-n-butyl ether and tetrahydrofuran. When the unsaturated alkyl group to be introduced is an alk-(1)-inyl group, the metal alkyl compound can also be an alkali acetylide, e.g., lithium, sodium and potassium acetylide. This ethinylation is conventionally conducted in ammonia or in a liquid amine, e.g., ethylene-diamine, or is carried out by reacting the corresponding 17-keto compound with acetylene in the presence of an alcoholate of a tertiary alcohol.

The l7a-ethinyl compounds of general Formula II can be converted into the corresponding 17a-vinyl and 17aethyl steroids of Formula II by hydrogenation. This hydrogenation, as is known, is preferably conducted by reacting the 17a-ethinyl compounds with hydrogen in the presence of a hydrogenation catalyst. Examples of suitable hydrogenation catalysts are palladium and platinum oxide catalysts.

In the alkylation of 3fl-acyloxy-15a,16u-methylene-5- androsten-17-ones, the alkyl group is stereospecifically introduced at the 17-position with the desired a-configuration. This stereospecific course of the reaction is surprising, since the alkyl residues are introduced in cis-position relationship with respect to the 15a,16a-methylene ring. It would be expected that the methylene group, due to steric hindrance, would hinder introduction of the alkyl groups into the 17OL-POSltlOH, whereby the formation of the isomeric 17,8-alkyl steroids would be favored.

Accordingly, in a process aspect, this invention relates to a process for the preparation of 15a,16a-methylene steroids of the general Formula Ia wherein R' represents a saturated or unsaturated lower alkyl residue, and R has the values given above, which comprises the steps of reacting a 3B-acyloxy-l5u,16amethylene-S-androsten-l7-one with a metal alkyl compound, alkyl being saturated or unsaturated; and oxidizing, optionally after hydrogenating a 17a-alkinyl group, if present, the B-hydroxy group of the thus-formed compounds of general Formula Ila (H wherein R has the values given above, to a 3-keto group and, optionally thereafter, esterifying a free l7a-hydroxy group, to a l7-ester group.

The starting compounds of general Formula II Wherein R is a hydrogen atom can be produced by reduction of a,l6a-methylene-4-androstene-3,17-dione with a complex metal hydride, e.g., sodium borohydride, lithium aluminum hydride and lithium tritert.-butoxyaluminohydride. During the reduction, the 17,8-hydroxy compound is formed stereospecifically. This course of the reduction is surprising, since the thus-introduced hydrogen atom enters at the cis-position with regard to the 15a,160tmethylene group. It would be expected that the methylene group, due to steric hindrance, would make it diflicult to introduce a hydrogen atom in the 170t-POSltlOI1.

-In another process aspect, this invention relates to a process for the production of l5ct,l6a-methylene steroids of the general Formula Ib ICE,

wherein R' is a hydrogen atom or acyl, which comprises the steps of reducing 15u,16et-methylene-4-an stene-3,17-dione with a complex metal hydride, and oxidizing the B-hydroxy group of the thus-formed compound of general Formula I-Ib HONN Hb to a 3-keto group and, optionally, thereafter esterifying the free l7B-hydroxy group.

The novel 3B-acyloxy-l5a,l6a-methylene-5-androsten- 17-ones and the 15a,16a-methylene-4-androstene-3,17- dione which serve as the starting compounds for the above-mentioned processes, can be produced, e.g. from a 3-monoester of 313,17u-dihydroxy-5,15-pregnadiene-- one by reduction of the '20-keto group to a hydroxy group, heating the thus-produced 3f3-acyloxy-5,l5-preg nadiene-l7ix,20a-diol with methylene iodide and zinccopper to produce the corresponding l5a,1-6a-methylene compound, oxidation of the thus-produced BB-acyloxy- 1511,16ot-methylene-5-pregnene-17u,20v-diol, e.g., with chromic acid, to the corresponding 17-keto compound; hydrolyzing the 3-acyloxy group of the thus-produced 3;8-acyloxy-15a,16a methylene-S-androsten-17-one; and then oxidizing the 3-hydroxy group to a 3-keto group, thus producing l5u,l6a-methylene-4-androsten-3,17-dione.

8.0 g. of l7a-hydroxy-3fi-acetoxy-S,l5-pregnadien-20- one is mixed with ml. of tetrahydrofuran and 16 g. of lithium tri-tert.-butoxyaluminohydride (lithium tritert.-butoxyalanate) and agitated for one hour at room temperature. Then, the reaction mixture is poured into weakly mineral-acidic ice water and extracted with methylene chloride. The methylene chloride phase is washed with water, dried, and concentrated under vacuum. The residue is recrystallized from diisopropyl ether, thus 0btaining 6.2 g. of SB-acetoxy-S,15-pregnadiene-17a,20adiol, M.P. 1685- C.

6.0 g. of 3B-acetoxy-5,1S-pregnadiene-17a,20a-diol in 120 ml. of absolute ether and 120 ml. of absolute ethylene glycol dimethyl ether is heated under reflux with 9.7 ml. of methylene iodide and 12 g. of zinc-copper for four hours. Then, the reaction mixture is filtered off from the inorganic solids and the latter is washed with methylene chloride. The organic phase is Washed with ammonium chloride solution and water, dried and concentrated under vacuum. The residue is recrystallized from diisopropyl ether, thus producing 4.6 g. of 3B- acetoxy-l5m,l6ot methylene-5 pregnene-l7a,20r-diol, M.P. 182-202" C.

3.0 g. of Bfi-acetoxy-l5a,16a-methylene-5-pregene-17a, 20a-diol is mixed with 150 ml. of acetone and 3.75. ml. of chromosulfuric acid (produced from 26.7 g. of chromium trioxide and 23 ml. of concentrated sulfuric acid, and diluted with water to 100 ml.). The reaction mixture is stirred at 0 C for 15 minutes The reaction mixture is then introduced into ice water. The thus-precipitated sediment is vacuum-filtered, Washed and dried. The crude product is chromatographed over a silica gel column. After recrystallization of the eluted product from diiso propyl ether, there is obtained 1.2 g. of 3fl-acetoxy-l5a, 16ot-methylene-5-androsten-17-one, M.P. l53154 C.

1.1 g. of 3,6-acetoxy-l5ot,l6ot-methylene-5-androsten- 17-one is mixed with 22 ml. of methanol, 2.2 ml. of water and 1.1 g. of potassium carbonate and refluxed for one hour. Thereafter, the mixture is neutralized with acetic acid and poured into ice water. The precipitate is vacuumfiltered, washed with water and dried. There is thus obtained 980 mg. of SB-hydroxy-lSaJ6u-methylene-5-androsten-17-one as a crude product.

900 mg. of 3fl-hydroxy-15a,16a-methyIene-S-androsten- 17-one, as the crude product, is mixed with 45 ml. of absolute toluene, 1.8 ml. of cyclohexanone and a solution of mg. of aluminum isopropylate in 2 ml. of absolute toluene. The reaction mixture is heated for 45 minutes, so that it gradually distills. The reaction mixture is then diluted with benzene, the organic phase is washed with dilute sulfuric acid and water and the solvents are removed by steam distillation. The thus-precipitated reaction product is vacuum-filtered, dried and recrystallized from diisopropyl ether, thus obtaining 720 mg. of 150:, 16a-methylene-4-androstene-3,17-dione, M.P. 191-194" C.

Example 1 700 mg. of 15a,16a-methylene-4-androstene-3,l7-dione is mixed with 50 ml. of tetrahydrofuran and 2.75 mg. of lithium tri-tert.-butoxyalanate and agitated at room temerature for one hour. Then, the reaction mixture is poured into ice water, slightly acidified with a mineral acid. The mixture is extracted with methylene chloride, the methylene chloride phase is washed with water, dried, concentrated under vacuum, and 690 mg. of 15u,16a-methylene-4-androstene-3cr,17fl-diol is thus obtained in the form of a crude product.

690 mg. of a,16a-methylene-4-androstene-3a,175-diol is mixed with 35 ml. of absolute dioxane and 690 mg. of dichlorodicyanobenzoquinone and stored for 16 hours at room temperature. Then, the reaction mixture is poured into a saturated sodium bicarbonate, solution, extracted with chloroform, the chloroform phase Washed with water and concentrated, thus obtaining 17fi-hydroxy-15ot, 16a-methylene-4androsten-3-one as the crude product. Melting point: 198.5-202 C. (from diisopropyl ether).

500 mg. of 17fi-hydroxy-15a,16a-methylene-4-androsten-3-one is mixed with 2 ml. of absolute pyridine and 1 ml. of acetic anhydride and stored at room temperature for 18 hours. Thereafter, the reaction mixture is poured into ice water, the precipitate is vacuum-filtered, washed with Water, dried, and recrystallized from diisopropyl ether, thus producing 360 mg. of 17,8-acetoxy-15a,16amethylene-4-androsten-3-one, M.P. 180.5182 C.

Example 2 350 mg. of 17 3 hydroxy 15a,16a methylene-4- androsten-3-one is mixed with 1.4 ml. of absolute pyridine and 0.7 ml. of propionic anhydride and allowed to stand for two days at room temperature. Thereafter, the reaction mixture is poured into ice water, the precipitate is vacuum-filtered, washed with water, and dried, thus obtaining 370 mg. of 17B-propionyloxy15a,16a-methylene-4- androsten-3-one, M.P. 121-122 C. (from hexane).

Example 3 470 mg. of 17/3 hydroxy 150:,1600 methylene-4- androsten-S-one is mixed with 2 ml. of absolute pyridine and 1 ml. of enanthic anhydride and heated for 90 minutes to 125 C. Then, the reaction mixture is poured into water, and the solvent is removed by steam distillation. Thereafter, the aqueous phase is extracted with methylene chloride, the methylene chloride phase is dried, concentrated under vacuum, and 510 mg. of 1713- heptanoyloxy-15a,16a-methylene-4 androsten-3 one is thus obtained in the form of an oil.

Example 4 400 mg. of 175 hydroxy 150:,16oc methylene-4- androsten-3-one is dissolved in 2 ml. of absolute pyridine, 1 ml. of capric acid chloride, and 2 ml. of absolute benzene and stored for hours at 5 C. After working up the reaction mixture as described in Example 3, 450 mg. of 17,6-decauoyloxy-15a,16a-methylene-4-androsten- 3-one is obtained as an oil.

Example 5 300 mg. of 175 hydroxy 15u,16a methylene-4- androsten-3-one is mixed with 1.5 ml. of absolute pyridine and 0.75 ml. of cyclopentylpropionic anhydride and heated for three hours to 125 C. After the reaction mixture has been worked up as disclosed in Example 3, 320 mg. of 17p-(3'-cyclopentylpropionyloxy)-15a,16a-methylene-4-androsten-3-one is obtained.

Example 6 1.0 g. of 3;8-acetoxy-15a,16a-methylene-5-androsten- 17-one is dissolved in 60 ml. of absolute benzene and introduced into a Grignard solution (produced from 1 g. of magnesium filings, 2.97 ml. of methyl iodide, and 40 ml. of absolute ether); the mixture is stirred for four hours at room temperature. Then, the reaction mixture is mixed with saturated ammonium chloride solutions; the aqueous phase is separated and extracted with ether. The combined organic phases are washed with Water, dried, and concentrated, thus obtaining 950 mg. of 17a-methyl- 15a,16a-methylene-5-androsten-3fi,17/3-diol.

900 mg. of 17oz methyl 15a,16u methylene-5- androstene-3/3,17fi-diol is mixed with 45 ml. of absolute toluene, 1.8 ml. of cyclohexane, and a solution of 180 mg.

of aluminum isopropylate in 2 ml. of absolute toluene; the mixture is heated for 45 minutes so that the solvent is gradually distilled off. Then, the reaction mixture is diluted with benzene, the organic phases are washed with dilute sulfuric acid and water, and the solvents are removed by steam distillation. Thereafter, the thus-deposited precipitate is vacuum-filtered, Washed with water, and dried, thus obtaining 800mg. of 17fi-hydroxy-17ot-methyl- 15a,16ot-IIlEthYlGIlC-4-fl11dl'08t6Il-3'OIIC, M.P. 169171 C. (from diisopropyl ether).

Example 7 Acetylene is introduced into a Grignard solution (produced from 1.0 g. of magnesium filings, 3.25 ml. of ethyl bromide, and 15 ml. of absolute tetrahydrofuran), cooled to 0 C. Then, this solution is mixed dropwise with a solution of 2 g. of 3fl-acetoxy15a,l6a-methylene-5-androsten- 17-one in 40 ml. of absolute tetrahydrofuran, and the mixture is thereafter agitated for 5 hours at room temperature. After working up the reaction mixture as set forth in Example 6, 1.9 g. of 17a-ethinyl-15a,l6a-methylene- 5-androstene-3[3,17B-diol is obtained.

900 mg. of 17a ethinyl 15:1,161: methylene-5- androstene-3B,17,H-diol is oxidized, as described in Example 6, with cyclohexanone and aluminum isopropylate. After Working up the reaction mixture as disclosed in Example 6, and chromatographing the thus-obtained crude product over a silica gel column, 600 mg. of 1713- hydroxy 17a ethinyl 15a,16a-methylene-4-androsten- 3-one is obtained, M.P. 214.52l6.5 C. (from diisopropyl ether).

Example 8 900 mg. of 170: ethinyl 15a,16a methylene-5- androstene-3p,17B-diol is hydrogenated with 15 ml. of thiophene-free benzene and 900 mg. of palladium catalyst according to Lindlar with 2 equivalents of hydrogen. Then, the catalyst is filtered off, the solution is concentrated to dryness, and the product thus obtained is 170: ethyl methylene-S-androstene-Ilfl,175- diol.

The thus-produced 17a ethyl ISuJGa-methyIene-S- androstene-318,17p-diol is oxidized, as described in Example 6, with cyclohexanone and aluminum isopropylate. After the reaction mixture has been Worked up as set forth in Example 6, and after the thus-obtained crude product has been chromatographed over a silica gel column, 520 mg. of 17/8-hydroxy-17a-ethyl-15a,16amethylene-4-androsten-3-one is obtained, M.P. 186.5- 188 C. (from diisopropyl ether).

The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

What is claimed is:

1. 15a,16u-methylene steroids of the formula wherein R is a hydrogen atom or a saturated or unsaturated lower-alkyl group of 1-4 carbon atoms, and 17- hydrocarbon carboxylic acid esters thereof containing 1-15 carbon atoms.

2. A 17-hydroxy compound of claim 1.

10 3. A compound of claim 1 wherein R is H. 14. A compound of claim 1, 17 8-decanoyloxy-15a,16u- 4. A compound of claim 1 wherein R is a saturated methylene-4-androsten-3-onc. lower 'alkyl group. 15. A compound of claim 1, 17p-(3'-cyclopentyl- 5. A compound of claim 1 wherein R is CECH. propionyloxy)-l5a,16u-methylene-4-androsten-3-one. 6. An alkanoic acid ester of claim 1. 5 7. A compound of claim 1, l7j3-hydroxy-l7a-ethinyl- References Cited 15a,16a-methylene-4-androsten-3-one. UNITED STATES PATENTS A if i f cliim 2 877 242 3/1959 Sondheimer et 21 260397 45 a-me yene- -an ros en- -one. I v 9. A compound of claim- 1, l7p-hydroxy-l7a-methylm et a1 322L232 3 202 684 8/1965 Burn etal 260 397 s 1 2 A cfmpmnd o; claun 1, 171 -hydroxy-15u,16a- 3,275,666 9/1966 Siegmam, 260:397 5 me yene- -an rosten- -one.

11. A compound of claim 1, l7fi-acetoxy-15a,l6a- 3318924 5/1967 Georglan 260-4074 methylene-4-androsten-3-0ne.

12. A compound of claim 1, l7fl-propionyloxy-l5a,16w 15 HENRY FRENCH Pnmary Exammer methylene-4-androsten-3-one. U S Cl X R 13. A compound of claim 1, 17fl heptanoyloxy-15a,16amethylene-4-androsten-3-one. 260-3974, 397.5; 424--243 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,749,742 D d July 31, 1973 Inventor(s) Rudolf Wlecherti et all.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

IN TABLE 1, COLUMN 2, UNDER "Levetor ani", across from I n a 0 0' 0 Q I o I 239 o Signed end sealed this 24th day of September 1974.

(SEAL) Attest:

McCOY M. GIBSON JR. Attesting Officer C. MARSHALL DANN Commissioner of Patents FORM po'wso (o-69) uscoMM-Dc 60376-P69 I t U,5I GOVERNNE NT PRINTING OFFICE 1 I969 0-355-33L 

